title: Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy.
abstract: BACKGROUND
  Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established.
  
  
  METHODS
  Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent.
  
  
  CONCLUSIONS
  This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies.
authors.affiliation: Laboratory for Molecular Medicine, 65 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: McLaughlin
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Kelly
authors.forename: Pamela P
authors.initials: PP
authors.lastname: Hawley
authors.forename: Basil T
authors.initials: BT
authors.lastname: Darras
authors.forename: Birgit
authors.initials: B
authors.lastname: Funke
authors.forename: Jonathan
authors.initials: J
authors.lastname: Picker
mesh_terms: D000328:Adult; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D003893:Desmin / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D003893:Desmin